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New Frontiers and Evolving Perspectives
The Science and Medicine of
Sepsis Management
The Role of Inflammation, Signaling Cascades, and
Immune Modulation on the Natural History and Treatment
of the Sepsis Syndrome
Dr. Steven Opal, MD
Program Chair and Moderator
Chairman Elect, International Sepsis Forum
Professor of Medicine at Brown Medical School
Director of the Infectious Disease Division
Memorial Hospital of Rhode Island
Pawtucket, Rhode Island, USA
Welcome and Program Overview
CME-certified symposium jointly
sponsored by the Postgraduate
Institute of Medicine and
CMEducation Resources, LLC
Commercial Support: Sponsored by
an independent educational grant
from Eisai, Inc.
Faculty disclosures: Listed in
program syllabus
Distinguished Program Faculty
Program Chair and Moderator
Dr. Steven Opal, MD
Dr. Pierre-Francois Laterre
Chairman Elect, International Sepsis Forum
Professor of Medicine at Brown Medical School
Director of the Infectious Disease Division
Memorial Hospital of Rhode Island
Pawtucket, Rhode Island, USA
Professor of Critical Care
St Luc University Hospital
Universite Catholique de Louvain
Brussels, Belgium
Dr. Jean-Paul Mira, MD, PhD
Professor of Critical Care Medicine
Chair, Medical Intensive Care Unit
Head, Variability of Innate Immunity
Research Laboratory
Cochin-St. Vincent de Paul University
Hospital
Paris, France
The Evolving Science and Medicine of
Sepsis Management
Evolving Perspectives in Sepsis Research:
The Pivotal Role of Immune Modulation
and the Unregulated Inflammatory Cascade
Dr. Steven Opal, MD
Program Chair and Moderator
Chairman Elect, International Sepsis Forum
Professor of Medicine at Brown Medical School
Director of the Infectious Disease Division
Memorial Hospital of Rhode Island
Pawtucket, Rhode Island, USA
Sepsis: Defining a Disease Continuum
Infection/Trauma
SIRS
► A clinical response arising
from a nonspecific insult,
including ³2 of the following:
► Temperature ≥38oC or ≤36oC
► HR ≥90 beats/min
► Respirations ≥20/min
► WBC count ≥12,000/mm3 or
≤4,000/mm3 or >10%
immature neutrophils
Sepsis
Severe Sepsis
► SIRS with a presumed or
confirmed infectious process
SIRS = systemic inflammatory response
syndrome.
Bone et al. Chest. 1992;101:1644
Sepsis: Defining a Disease Continuum
Infection/Trauma
SIRS
Sepsis
Severe Sepsis
Sepsis with ≥1 sign of organ
failure
– Cardiovascular (refractory
hypotension)
Shock
– Renal
– Respiratory
– Hepatic
– Hematologic
– CNS
– Unexplained metabolic acidosis
Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207.
Challenges to Research and Study
Infection/Trauma
►
►
►
►
►
►
SIRS
Sepsis
Severe Sepsis
High and variable mortality rate (20-60%)
Heterogeneous patient population
Unpredictable disease progression
Unclear etiology and pathogenesis
Based on inflammation as cause, regardless of source
Knowledge base has progressed since 1992
Sepsis Resuscitation Bundle (6 Hours)
1.
2.
3.
4.
Serum lactate measured
Blood cultures obtained prior to antibiotic administration
From the time of presentation, broad-spectrum antibiotics
administered within 3 hours for ED admissions and 1 hour for non-ED
ICU admissions
In the event of hypotension and/or lactate > 4 mmol/L (36 mg/dl):
a)
b)
5.
Deliver an initial minimum of 20 ml/kg of crystalloid (or colloid
equivalent)
Apply vasopressors for hypotension not responding to initial fluid
resuscitation to maintain mean arterial pressure (MAP) > 65 mm Hg
In the event of persistent hypotension despite fluid resuscitation
(septic shock) and/or lactate > 4 mmol/L (36 mg/dl):
a)
b)
Achieve ventral venous pressure (CVP) of > 8 mm Hg
Achieve central venous oxygen saturation (ScvO2) of > 70%*
* Achieving a mixed venous oxygen saturation (ScvO2) of 65% is an acceptable alternative
Copyright 2007 by SCCM, ESICM, and the International Sepsis Forum
Sepsis Management Bundle (24 Hours)
1. Low-dose steroids administered for septic shock in
accordance with a standardized ICU policy
2. Recombinant Activated protein C administered in
accordance with a standardized ICU policy
3. Glucose control maintained > lower limit of normal, but
< 150 mg/dl (8.3 mmol/L)
4. Inspiratory plateau pressures maintained < 30 cm H2) for
mechanically ventilated patients
Copyright 2007 by SCCM, ESICM, and the International Sepsis Forum
Pathophysiology of Sepsis
Riedemann NC et al. Nature Medicine 2003;9:517-524
The Apoptosis Theory of Sepsis
►
Massive apoptosis of lymphocytes is seen
in lymphoid tissues of animals and
humans with sepsis
►
Later phase of immunosuppression may
in part be due to apoptosis
►
Secondary nosocomial infection and/or
viral re-activation
Hotchkiss RS et al. 1999-2009
Schemata for Pathophysiology of Sepsis
Rittirsch D et al. 2008
The Science and Medicine of Sepsis
What do we know about the immunopathophysiology of sepsis?
►
All encompassing single mechanism still elusive
►
Host inflammation hypothesized to be the cause of
the syndrome
►
Natural experiment with mice suggests that we may
be able to reduce inflammation without
compromising host defense, perhaps through
manipulation of TLRs
SEPSIS: A Dynamic, Complex Host Response to PAMP/DAMPs
DAMPs
PAMPs
Microorganisms
PRRs
Immune cells
TLRs
NOD-LRRs
RLHs
HSP
Heparan
Sulfate
Hyaluronic
acid
Fibrinogen
Biglycan
Surfactant A
HMGB-1
Heme
MRP8/14
ASC
NF-κB
Host-derived mediators
Cinel& Opal CCM 2009;37:291
Caspase-1 & 5
ASC
NALP1 & 3
Pyrin
Incidence of Severe Sepsis by Age
100,000
Number of cases
25
Cases
Incidence rate
80,000
20
60,000
15
40,000
10
20,000
5
0
0
<1 1 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+
Age/Years
Angus DC, at al. Crit Care Med 2001; 29:1303 10.
Incidence/1,000 Population
30
120,000
Sepsis-targeting
the host
response
Receptor downregulation (TLR 4, TNFR, HLA-DR)
Soluble (sIL1,6,TNFr) and decoy receptors (IL-1R2)
Receptor antagonists (IL-1ra)
Anti-inflammatory cytokines (IL-4,10,13)
Intracellular inhibitors (SOCS, IkB, Tollip, MyD88s)
Cellular apoptosis of B cells CD4 T cells and FDCs
Sepsis-induced immunosuppression
Hotchkiss and Karl NEJM 2003;348:138
Sepsis-targeting microbial
mediators-LPS
4 million LPS molecules/cell - 75%
of outer membrane
Increasing Levels of Endotoxemia
Aggravates Severity of Illness
<0.4
0.4-0.6
>0.6
(n=367)
(n=228)
(n=262)
5
5
7
P=0.04
13.3
15.3
17.6
P<0.001
% Hospital Death
16
23
23
P=0.05
% ICU Death
11
13
17
P=0.04
WBC (% abnormal)
42
48
56
P<0.001
% with Shock
12
21
23
P<0.001
% Hypoxemic
42
52
56
P=0.005
ICU LOS (days)
APACHE II
P*
*p values compare < 0.4 vs > 0.6
Marshall et al. the Medic trial J Infect Dis 2004;190:527
LPS
LPS
Mj
Mj
3’
Early Signaling Events of
Innate Immunity are now
increasingly understood
3’
Host response-antimicrobial
defense programs
NFkB
NFkB
5’
5’
DNA
DNA

nuclear
localization
sequence
LPS-mediated
gene induction
MD-2
CD 14
TLR4
TIR
tk, mapk
NFkB
Signal transduction
MONOCYTEMACROPHAGE
Lowry et al. Nature 2005;437:1032-7
3714 genes (12% of the
human transcriptome) is
altered over 24 hours
upon exposure to LPS
Cytokines
Chemokines
Nitric oxide
Acute phase proteins
Pro-coagulants
The Hexameric TLR4–MD-2–LPS
Signalling Complex
Lipid A
BS Park et al. Nature 2009; 7830:1-5
The main
trimerization
interface
of the TLR4–MD2–LPS complex
BS Park et al. Nature (2009);7830
Structural Comparison of LPS with Antagonists
TLR4
binding
site
BS Park et al. Nature (2009); 7830:1-5
Current Anti-LPS projects for severe infection
• Currently in use-PMX B hemoperfusion columns
• Phase 3 trials-E5564
• Phase 2 trials-recombinant Lactoferrin
• Preclinical/early clinical study: AOAH transgenes, rAlkaline
phosphatase, small molecule inhibitors, cationic peptides,
heme absorption columns, monoclonal antibodies, receptor
fusion constructs
O-side
chain
oligosaccharide
Lipid A
Inner core
Outer core
E. coli
Lipopolysaccharide
Prophylactic and Salvage Rx with anti-TLR4 antibodies protect mice
from lethal Gram-negative bacterial sepsis (E. coli 018 given i.p.)
-15 min
109cfu
-15 min
-159min
10 9cfu
10 cfu
+13 hr
109cfu
+13hr
hr
+13
1055cfu
cfu
10
Roger T et al. PNAS 2009;106:2348-2352
With gentamicin and ceftriaxone
Packed Crystal Structure of Human Lactoferrin
Suzuki et al J Mol Biol 2003; 331:485
Lactoferrin LF11 Peptide Bound to LPS
Cationic region
Lactoferrin
LPS
Phosphoryl
group
Lipid A
Cationic LPS binding
protein-competes for LPS
with LBP, CD14
Fe++ chelator, limits
oxidant tissue injury
Bacteristatic
Promotes neutrophil
binding and activity
Promotes efficient
antigen presentation and
clearance by GALT
Phase 2 clinical trials in
prevention of neonatal
sepsis positive, adult
study results completed
Japelj et al. J. Biol. Chem. 2005;280:16955
Phase II Results with Oral Talactoferrin
in Severe Sepsis
p<0.04
p=0.06
Total (n=190)
Agennix AG Press Release Dec. 1, 2009
No cardiovascular dysfunction
(n=69)
PMX Cartridge for Clinical Application
Approved for use in Japan for many years and available on a limited
basis in several European countries
Estimation of Survival Rate According to
Treatment Group
Polymyxin B hemoperfusion therapy
Survival Proportion
1.00
0.75
0.50
Conventional therapy
0.25
Log-rank P=.03
0
No. at risk
Polymyxin B hemoperfusion therapy
Conventional therapy
5
10
15
20
25
30
22
12
18
11
Time, d
34
30
34
22
32
19
30
15
27
15
Patients with septic shock secondary to Peritonitis
Cruz, D. N. et al. JAMA 2009;301:2445
Physiological End Points by Treatment
Group at Baseline and 72 Hours
Severely septic patients with peritonitis
Cruz, D. N. et al. JAMA 2009;301:2445
Jung et al. PLoS One
2009;4(1):e704
Jung et al. PLoS One
2009;4(1):e704
Conclusions
New Approaches for Treating Sepsis Using
Novel Interventions Against Old Targets
► The discovery of the TLRs and other pattern recognition receptors
of the innate immune system offers new treatment options to the
initiating events in severe sepsis
► Targeting microbial mediators and their signaling receptors is a
rational and probably safe approach to treat sepsis
► The results of current ongoing clinical trials targeting microbial
ligands and their receptors will answer longstanding questions
about adjuvant therapies to improve the outcome in sepsis
► We will next hear from two experts in sepsis research:
●
Jean-Paul Mira (Toll like receptors)
●
Pierre-Francois Laterre (Clinical development of TLR4 inhibitors)
The Science and Medicine of
Sepsis Management
Toll-Like Receptors in Sepsis
Emerging Implications for Critical Care Management
Dr. Jean-Paul Mira, MD, PhD
Professor of Critical Care Medicine
Chair, Medical Intensive Care Unit
Head, Variability of Innate Immunity
Research Laboratory
Cochin-St. Vincent de Paul University Hospital
Paris, France
Recognition of PAMPs from Different
Classes of Microbial Pathogens
Mogensen TH. Clin. Microbiol. Rev.2009; 22 : 240-273
Kumar H. Biochem Biophys Res Comm. 2009;388:621
Akira S, 2009
TLRs: Receptors of Alarmins
EMBO reports 2006;7:775
Known Endogenous TLR Ligands
Bianchi M. J Leuk Biol 2007
TLR Recognition of Exogenous versus
Endogenous Ligands
Iwasaki A. Science 2010; 327:291
Canonical model
of sepsis
New model of sepsis
Animal Models of Sepsis
TLR2 and Streptococcus pneumoniae
Meningitis
WT
TLR2
-/-
Echchannaoui H et al. JID 2002;186:798
Tissieres P. Curr Opinion Infect Dis 2009;22:285
Essential Role of MD2 in LPS
Responsiveness
MD-2 -/-
10
8
Surivival (# of mice)
Surivival (# of mice)
8
MD-2 -/6
4
2
WT
4
4
2
WT
0
0
0
10
20
30
40
Hours
LPS IP + D-galactosamine IP
Nagai H. Nat Immunol 2002;3:667
50
0
1 2 3 4 5 6 7
Days
LPS IP
Essential Role of MD2 in
Gram Negative Infection
WT
Survival (# of mice)
10
8
6
4
2
MD-2 -/-
0
0
5
10
Days
Salmonella Peritonitis
Nagai H. Nat Immunol 2002;3:667
15
Relevance of Polymorphisms in
TLR and TLR Adapters for Sepsis
Understanding the Role of TLR Signaling in
Susceptibility to Human Infections
Human monogenic immunodeficiencies affecting Toll-like receptor function
Clinical
immunodeficiency
Mutated
gene
Mutated
protein
Immunological
pathways
affected
Infectious susceptibility
Pyogenic bacterial
infections (Streptococcus
X-lined recessive
EDA-ID
IKBKG
IKKƴ(NE
MO)
Multiple innate
and adaptive
pathways
pneumoniae,
Staphylococcus aureus,
Haemophilus influenzae)
Atypical mycobacteria
(Mycobacterium avium
intracellulare)
Autosomal
dominant EDA-ID
IRAK4 deficiency
NFKBIA
IRAK4
IκBα
IRAK4
Multiple innate
and adaptive
pathways
TLR signaling
As above
Pyogenic bacterial
infections (Streptococcus
pneumoniae,
Staphylococcus aureus)
Pyogenic Bacterial Infections in
Humans with IRAK-4 Deficiency
Pyogenic Bacterial Infections in
Humans with IRAK-4 Deficiency
IL-1a (pg/ml)
40
20
WT/WT
WT/Asp299Gly
&
Thr399Ile
TLR4 Polymorphisms and Septic Shock
% TLR4 mutated patients
30
25
20
15
10
5
0
Gram negative
Septic shock
Lorenz , Arch. Intern. Med. 2002 162:1028
Control
Toll-like Receptor 4 Polymorphisms and
Aspergillosis in Stem-Cell Transplantation
Hypothesis : polymorphisms in TLR genes from the donor and the
recipient may influence susceptibility to invasive aspergillosis in stem cell
transplantation
Discovery study: DNA from 336 patients and their unrelated donors
(1995 – 2003)
33 cases of aspergillosis
Validation study: matched case-control study with recipients of donors
103 patients with invasive aspergillosis and 263 recipients without
aspergillosis.
Genes: 20 SNPs in TLR2, TLR3, TLR4 and TLR9
Bochud PY. N Engl J Med 2008; 359:1766
Toll-like Receptor 4 Polymorphisms and
Aspergillosis in Stem-Cell Transplantation
Bochud PY. N Engl J Med 2008; 359:1766
Legionnaire’s Disease and TLR5
Common TLR5 Stop Codon Polymorphism
Hawn TR. J Exp Med 2003; 198: 1563
1174
1775
C
C
A
G
T
T
A
G
TLR5 Polymorphisms and Legionnaire’s Disease
18
Cases
Cas
n=109
CTL n=508
CTL
Paired
CTL n=89 No. BP
appariés
CTL
16
Allele OR (95% CI)
Smokers
P
Nonsmokers
P
OR (95% CI)
Haplotype 1174-1775
14
12
SNP
P = 0.02
10
CA
00 1
1
CG
01 1.33 (0.55, 3.25)
0.53
1.99 (1.04, 3.80)
0.04
TA
10 0.76 (0.19, 3.05)
0.70
2.43 (1.00, 5.89)
0.005
8
6
P = 0.03
4
2
0
CG
Hawn TR. J Exp Med 2003; 198: 1563
TA
1174
C
C
1775
A
G
T
T
A
G
IRAK-1 Haplotype Increases
NF-kB Activation
150
P=0.0009
AUC
100
IRAK-1 gene located on X chromosome
50
2 haplotypes: htSNP = IRAK-1 532LS
0
Arcoli J. Am J Respir Crit Care Med 2006;175:1335
Variant
Wildtype
IRAK-1 Haplotype
IRAK-1 Haplotype Increases
Morbidity of Sepsis
20
P=0.03
VFD
155 septic Caucasians patients
10
Shock
70
0
P=0.047
60
Wildtype
Variant
IRAK-1 Haplotype
20
%
50
Pulmonary Infection
40
30
20
VFD
P=0.02
10
10
0
Variant
Wildtype
IRAK-1 Haplotype
0
Wildtype
Variant
IRAK-1 Haplotype
OR:2.6 (95% CI, 1.1-7.7)
Arcoli J. Am J Respir Crit Care Med 2006;175:1335
IRAK-1 Haplotype Increases
Mortality of Sepsis
60-Day Mortality
Pulmonary Infection
60-Day Mortality
70
P=0.03
60
50
50
40
40
%
%
60
70
30
P=0.05
30
20
20
10
10
0
0
Variant
Wildtype
IRAK-1 Haplotype
Arcoli J. Am J Respir Crit Care Med 2006;175:1335
Variant
Wildtype
IRAK-1 Haplotype
Contribution of Toll-like receptormediated responses to sepsis
pathogenesis
TLR signaling pathway: 84 genes expression analyzed
Mononuclear cells: down regulation in septic shock patients
Neutrophils: up-regulation throughout the stages of sepsis
Salamao R. Crit Care Med 2009; 37:132
Tissieres P. Curr Opinion Infect Dis 2009;22:285
Endotoxin Responsiveness of Human Airway
Epithelia is Limited by Low Expression of MD-2
Jia HP. Am J Physiol Lung Cell Mol Physiol 2004;287:L428
Soluble MD-2 Activity in Plasma from Patients
with Severe Sepsis and Septic Shock
Pugin J. Blood 2004; 104:4071
Increased Release of sMD-2 During Human Endotoxemia
and Sepsis: A Role for Endothelial Cells
WB anti-MD2
Healthy
Septic
Wolfs TG. Mol Immunol 2008;45:3268
Increased Release of sMD-2 During Human
Endotoxemia and Sepsis: A Role for Endothelial Cells
Endotoxemia in human volunteers
sMD-2 (mg/ml)
*
*
Time (hours)
Wolfs TG. Mol Immunol 2008;45:3268
*
*
Mean fluorescence
TLR4/vector
TLR4/vector(noLPS)
LPS decreases TLR4 cell expression
1.2
1
0.8
0.6
0.4
0.2
0 0
0.2
0.4
0.6
LPS (ug/ml)
Lauer S. Cell Immunol 2009;255:8
0.8
1.0
TLR4 cell surface expression
Soluble MD2 Increases TLR4 Levels on
the Epithelial Cell Surface
Endotoxin Responsiveness of Human Airway
Epithelia is Limited by Low Expression of MD-2
sMD2 may prime epithelial cells for enhanced immunoresponsive function
Jia HP. Am J Physiol Lung Cell Mol Physiol 2004;287:L428
Conclusions
► Cell response to pathogen stimulation is a complex
phenomenon!
► During sepsis, both exogenous and endogenous ligands
stimulate TLRs
► Effects of TLRs stimulation are cell-dependent
► Consequences of TLRs stimulation are host-dependent
► TLRs coreceptors and signaling molecules play a pivotal
role in the regulation of the inflammatory response
► Toll Like Receptors and TLR adaptors: attractive drug
targets
Emerging Perspectives in
Sepsis Management
Clinical Trials with
TLR inhibition in Sepsis
The Journey from the Bench to the Bedside
Dr. Pierre-Francois Laterre
Professor of Critical Care
St Luc University Hospital
Universite Catholique de Louvain
Brussels, Belgium
TLR4 Ligands
►
Pathogen-associated pattern molecules
●
●
►
LPS
Mannan
Danger-associated pattern molecules
●
●
●
●
●
HMGB1
Heat shock proteins
Hyaluronan
Biglycans
Fibronectin
Clinical Trials of Anti-TLR4 Agents
►
Agents targeting LPS
●
●
●
►
Antibodies against LPS
Polymyxin B
Bactericidal/Permeability-Increasing Protein
Agents targeting TLR4 or the TLR Signalsome
●
●
TAK-242
Eritoran
Eschericia coli
Lipopolysaccharide
O-side
chain
Oligosaccharide
Lipid A
Inner core
Outer core
Clinical Trials of Antibodies against
LPS Core Region Epitopes
Ann Intern Med 1994;120:771-78
P1 Proof-of-Concept Trial of Eritoran in Normal
Human Volunteers Challenged with LPS
100 and 250 mg doses of
eritoran completely blocked
all clinical signs and
symptoms of LPS toxicity
● Chills
● Fever
● Headache
● Myalgia
● Tachycardia
►
100 and 250 mg doses of
eritoran completely blocked
all biochemical effects of LPS
challenge
400
Plasma TNF α (pg/mL)
►
Lynn M, et al. J Infect Dis. 2003 Feb 15;187(4):631-9
350
300
250
200
Placebo
150
100
60, 100, 260 ug E6684
50
0
0
2
4
6
8
Time after LPS infusion (hrs)
10
Phase 2 Study of Eritoran
►
Multicentric,
randomized,
double-blind trial
Tidswell et al. Crit Care Med 2010; 38:72-83
Baseline Characteristics: P2 Eritoran
Tidswell et al. Crit Care Med 2010; 38:72-83
Characteristics of Infection: P2 Eritoran
Characteristic
Placebo
(n=96)
Eritoran
tetrasodium
Eritoran
tetrasodium
45mg (n=103)
105 mg (n=94)
Primary focus of infection, n (%)
Overall
p Value
.5054
Pulmonary
38 (39.6)
39 (37.9)
29 (31.2)
Intra-abdominal/gynecologic
20 (20.8)
14 (13.6)
15 (16.1)
Urinary tract
13 (13.5)
13 (12.6)
19 (19.4)
Skin/soft tissue
5 (5.2)
7 (6.8)
7 (7.5)
Indwelling catheter
2 92.1)
8 (7.8)
5 (5.4)
Unknown
3 (3.1)
8 (7.8)
9 (9.7)
Other
7 (7.2)
4 (3.9)
5 (5.4)
No evidence of infection
8 (8.3)
10 (9.7)
5 (5.4)
Tidswell et al. Crit Care Med 2010; 38:72-83
Characteristics of Infection: P2 Eritoran
(continued)
Characteristic
Placebo
(n=96)
Eritoran
tetrasodium
Eritoran
tetrasodium
45mg (n=103)
105 mg (n=94)
Infection type, m (%)
.6944
Gram-negative
26 (27.1)
23 (22.3)
29 (31.2)
Gram-positive
30 (31.3)
38 (36.9)
29 (31.2)
Mixed bacterial
10 (10.4)
7 (6.8)
13 (14.0)
Fungal
1 (1.0)
4 (3.9)
1 (1.1)
Viral
1 (1.0)
2 (1.9)
0 (0)
17 (17.7)
18 (17.5)
15 (16.1)
Bacteremia, without focal
infection, n (%)
3 (3.1)
10 (9.7)
8 (8.5)
Bacteremia,
with focal infection, n )%)
25 (26.1)
29 (28.1)
26 (27.7)
87 (91)
91 (88)
85 (90)
Unkown
Adequate antimicrobial
therapy, n (%)
Overall
p Value
Tidswell et al. Crit Care Med 2010; 38:72-83
Endotoxin in Critically Ill
J Marshall JID 2004
Endotoxin in Critically Ill
Gram-negative infection
Gram-positive infection
EA Level
Prevalence,
% (no./total)
OR
(95% CI)
Prevalence,
% (no./total)
OR
(95% CI)
Low (<0.40)
1.4 (5/367)
--
3.8 (14/367)
Intermediate
(0.40-0.60)
4.8 (11/228)
3/7
(1.3-10.7)
High (>0.60)
6.9 (18/262)
5.3
(2.0-14.6)
J Marshall JID 2004
All infections
Prevalence,
% (no./total)
OR
(95% CI)
--
5.2 (19/367)
--
7.9 (18/228)
2.2
(1.1-4.4)
11.4 (26/228)
2.4
(1.3-4.4)
5.7 (15/262)
1.5
(0.7-3.2)
10.7 (28/262)
2.2
(1.2-4.0)
Phase 2 Study of Eritoran
Multicentric, randomized,
double-blind trial
►
Placebo versus two eritoran
dosing regimens (45 mg/6 d or
105 mg/6 d)
►
Patients with severe sepsis and
predicted risk of mortality
(PROM) of 20-80% based on
APACHE II score
►
Study drug started within 12 h
of recognition of severe sepsis
►
300 patients randomized; 293
included in the intent to treat
(ITT) analysis
p = 0.335
Percent 28-day Mortality
►
Mortality in
modified intent-to-treat population
(n=293)
p = 0.846
Treatment Group
Tidswell et al. Crit Care Med 2010; 38:72-83
Eritoran P2 Clinical Trial
Prospectively Defined Subgroups
Mortality by Presence of Shock
P-0.105
P-0.913
P-0.503
P-0.083
APACHE II Quartile
Tidswell et al. Crit Care Med 2010; 38:72-83
Percent 28-day Mortality
Percent 28-day Mortality
Mortality by APACHE II Quartile
P=0.598
P=0.434
Presence of Shock at Baseline
Mortality in Important Subpopulations: P2
Clinically Evaluable Population
(n=235)
p = 0.036
Percent 28-day Mortality
p = 0.094
Treatment Group
Tidswell et al. Crit Care Med 2010; 38:72-83
N DAA (Xigris) Population
(n=225)
Kaplan-Meier Survival-Time Curves: P2
Tidswell et al. Crit Care Med 2010; 38:72-83
Relative Reduction in Risk of Death
at 28 Days and 95% CI: P2 Eritoran
MITT population
APACHE II predicted mortality
Low (20-50%)
High (51-80%)
Type of pathogen
Gran neg
Gram pos
Mixed bacterial
Other/unknown
Age
65 and younger
66 and older
Stage of study
Stage II
Stage III
0.10
Tidswell et al. Crit Care Med 2010; 38:72-83
1.0
10
Relative Reduction in Risk of Death
at 28 Days and 95% CI: P2 Eritoran (cont.)
Xigra Used
Yes
No
Baseline Endotoxin
Detectable
Elevated > 0.2 endotoxin status
Baseline HDL
< 25 mg/dL
> 25 mg/dL
Time to drug infusion
8 hours or less
More than 8 hours
0.10
Tidswell et al. Crit Care Med 2010; 38:72-83
1.0
10
Infectious Adverse Events: P2 Eritoran
Infectious Adverse
Events
Placebo
(n=96)
Eritoran
Tertrasodium
45 mg
Eritoran
Tetrasodium
105 mg
(n=103)
(n=94)
Overall
p value
Investigatorreported infectious
complication
50.5
45.6
37.0
.2001
Clinical evaluation
committee
determination of
infectious
complication
36.8
35.0
38.0
.8967
Infectious adverse events were defined as either a) recurrent infection
at the same site as the sepsis-initiating infection, either relapse of the
same organism, or superinfection by a different organism; or b) new
infection occurring at a different site that the sepsis-initiating infection.
Tidswell et al. Crit Care Med 2010; 38:72-83
Eritoran P2 Clinical Trial:
No Effect on Circulating IL-6 Concentration
IL-6 lvel (pg/mL)
100000
10000
1000
100
10
0
12 hr 48 hr
0
12 hr 48 hr
0
12 hr 48 hr
1
Placebo
Tidswell et al. Crit Care Med 2010; 38:72-83
45 mg
105 mg
ACCESS Trial: P3 Eritoran Trial
Controlled Comparison of Eritoran Tetrasodium and Placebo in
Patients with Severe Sepsis
A Phase 3, Multicenter, Randomized, DoubleBlind, Placebo-Controlled Study Evaluating
Eritoran Tetrasodium in Patients with Severe
Sepsis: Can Inhibition of TL-4 Improve AllCause Mortality in Patients with Severe Sepsis
• 159 worldwide study locations
• 2000 patients enrolled in trial
ACCESS Trial Protocol Overview: Study Objectives
Analysis of Efficacy Variables
Primary Efficacy Endpoint: All-cause mortality at Day 28. The difference in
mortality rates between treatment groups will be
tested by chi-squared test
Key Secondary Endpoint:
Mortality at 1 year
Other Endpoints of Interest:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Length of ICU stay within 28 days
Length of Hospital stay within 28 days
Duration of dialysis within 28 days
Duration of mechanical ventilation within 28 days
Duration of use of vasopressors within 28 days
Measurement of cytokine inflammatory panel and procalcitonin
Quality of Life
SOFA assessment
Incidence of infection episodes subsequent to randomization
Pharmacoeconomics
Mortality at 3 and 6 months
ACCESS Trial Entry Criteria
Inclusion Criteria
I. Age > 18 years; no upper age limit
II. Confirmed early onset of severe sepsis defined as:
• Objective evidence of infection – likely bacterial or fungal
pathogen
Examples of objective evidence:

Clinical findings (i.e. cellulitis or abscesses)

Cultures

Gram stains

X-rays

Surgical pathology specimens
** Note: A positive culture is not a requirement for entry into the trial
ACCESS Trial Entry Criteria
Inclusion Criteria
• Presence of at least 3 of 4 SIRS criteria:
— Core Temperature > 38C or < 36C
— Heart Rate > 90 beats/min
**Note: Patients who cannot be assessed for sepsis-induced tachycardia
due to another medical condition known to increase heart rate, or
those receiving treatment that prevents tachycardia, must have 2 of
the remaining 3 SIRS criteria.
— Respiratory Rate > 20 breaths/min OR a PaCO2 < 32 mmHg, or
mechanical ventilation
— WBC Count > 12,000 cells/L, < 4,000 cells/L, OR > 10% band
forms.
ACCESS Trial Entry Criteria
Inclusion Criteria
III.At least 1 of the following organ dysfunctions:
A. Acute Lung Injury (ALI)/Acute Respiratory Distress
Syndrome (ARDS)
— Acute Onset of the following:
1. PaO2/FiO2 < 300 (<200 in pts. with pneumonia). If altitude >
1000m, then PaO2/FiO2 < 300 x (PB/760)
2. Bilateral infiltrates consistent with pulmonary edema on frontal
chest x-ray. (Infiltrates may be patchy, diffuse, homogeneous, or
asymmetric)
3. Requirement for positive pressure ventilation via endotracheal
tube
4. No clinical evidence of left atrial hypertension
Criteria 1-4 must occur together within 24-hour interval
ACCESS Trial Entry Criteria
Inclusion Criteria
B. Thrombocytopenia
Acute onset of platelet count <100,000 or a reduction of 50% or
more from prior known levels, without past history of
thrombocytopenia, and without attributable cause other than
infection
C. Lactic Acidemia
Acute onset of serum lactate level > 4mmol/L (36 mg/dL)
(Protocol amendment-lactic acidosis >2.2mmol/L (19.8 mg/dL) and
evidence of metabolic acidosis: pH<7.30 or base deficit>5.0
mmol/L)
D. Acute Renal Failure
Urine output < 0.5 mL/kg/hr for at least 2 hrs, despite
administration of at least 500 mL of crystalloid or 200 mL of colloid
over a 30 minute period
ACCESS Trial Entry Criteria
Inclusion Criteria
E. Shock
Acute onset of systolic BP < 90 mmHg or MAP of < 65 mmHg. BP is
poorly responsive to initial aggressive fluid resuscitation with a
crystalloid or colloid, and vasopressors are required to maintain MAP >
65 mmHg despite initial fluid resuscitation for a least 1 hour.
Mechanically ventilated patients must exhibit hypotension due to sepsis
before the institution of mechanical ventilation or be hypotensive for at
least 60 min following intubation to qualify for the study on basis of
shock.
ACCESS Trial Entry Criteria
Inclusion Criteria
IV. A reasonable likelihood that administration of study
drug can be started within 12 hours of the time of
recognition of organ dysfunction.
V. Must be a commitment to full patient support
**Note: If a patient’s family has not committed to aggressive
management of patient’s condition or has requested the
patient be classified as “Do not resuscitate” or “Do not treat”,
the patient is excluded. If a family directive allows all
resuscitative efforts other than chest compressions, the patient
may be enrolled.
ACCESS Trial Entry Criteria
Inclusion Criteria
VI. APACHE II Score
Baseline APACHE II Score of 21-37, inclusive
The Clinical Coordinating Centers will be responsible
for calculating the APACHE II Scores and
enrolment approval
OSCCC (RI) and SLUCCC (Brussels).
ACCESS Trial Entry Criteria:
Time Window
Onset of Organ Failure
< 12 hrs between documentation of the 1st qualifying
organ dysfunction and administration of study drug
Onset of
1st Organ
Failure
12 hrs
Study Drug
Infusion
ACCESS Trial Protocol Overview
Prior & Concomitant Therapy
In addition to the appropriate antibiotic therapy, it is expected that
all patients will receive evidence-based appropriate treatment of
their severe sepsis.
Appropriate treatment modalities include, but are not limited to:

Initial resuscitation goals

Use of low tidal volumes for mechanical ventilation

Control of blood glucose levels

Maintenance of target hemoglobin levels

Source control
In countries where recombinant human activated Protein C is
approved for use, careful consideration should be given to
contraindications and locally approved indications for use.
ACCESS Trial: Current Status
►
Over 1600 subjects randomized
►
Enrolling ~40-60 subjects/month in recent
months
At 1400 Subjects
►
Mean APACHE II score ~27 in all regions of the
world
►
Mean age= 65
►
Median time to treatment = 9.3 hrs
Organ Dysfunctions:
~33% 1
~33% 2
~24% 3
50% Shock
25% Lactic Acidosis
Infection
►
Site of Infection?
●
●
●
►
~50% lung
~20% genitourinary
~20% abdominal
Incidence of new infection etc. (after 48 hours)
●
~43% …..similar to that reported by
investigators in the Phase II study (~47%)
Data Monitoring Reviews of Study
►
DMC reviews at 375 and 750 and 1100 subjects
resulted in recommendations to continue the
study
Summary and Conclusions
► TLR-4 inhibition represents a potentially promising strategy for
treatment of severe sepsis
► Phase II Study with eritoran is completed, peer-reviewed, and
published in JCCM
► There are signals in the Phase II eritoran study of improved
mortality outcomes in high-risk subgroups; and safety profiles
are acceptable
► Phase III ACCESS eritoran study is completing enrollment
* Three interim analyses have been conducted for the Phase III ACCESS
study and the DSMB has given authorization to complete the study
Summary and
Take Home Message
Conclusions
►
Despite its complexity and the multitude of
pathogens that can cause sepsis, a limited
number of pattern recognition receptors of the
innate immune system activate the systemic host
response in sepsis
►
The Toll like receptors are now major targets for
therapeutic intervention in sepsis.
►
Polymorphisms of TLRs and related adaptor and
signaling molecules are associated with
susceptibility or protection from a number of
infectious diseases
Conclusions
►
TLR4 is the signal receptor for LPS along with
MD2 and CD 14
►
A number of TLR 4 inhibitors show promise as
adjuvant therapies for sepsis; one TLR4 inhibitor,
known as eritoran or E5564, is now in late stage
clinical development.
►
If TLR inhibitors can improve survival in human
sepsis, they will likely be most effective given
early in the septic process. This is a major
challenge in clinical trial design and
implementation